Pathology of explanted pediatric hearts: An 11-year study. Population characteristics and implications for outcomes.

BACKGROUND: As more pediatric patients become candidates for heart transplantation (HT), understanding pathological predictors of outcome and the accuracy of the pretransplantation evaluation are important to optimize utilization of scarce donor organs and improve outcomes. The authors aimed to investigate explanted heart specimens to identify pathologic predictors that may affect cardiac allograft survival after HT. METHODS: Explanted pediatric hearts obtained over an 11-year period were analyzed to understand the patient demographics, indications for transplant, and the clinical-pathological factors. RESULTS: In this study, 149 explanted hearts, 46% congenital heart defects (CHD), were studied. CHD patients were younger and mean pulmonary artery pressure and resistance were significantly lower than in cardiomyopathy patients. Twenty-one died or underwent retransplantation (14.1%). Survival was significantly higher in the cardiomyopathy group at all follow-up intervals. There were more deaths and the 1-, 5- and 7-year survival was lower in patients ≤10 years of age at HT. Early rejection was significantly higher in CHD patients exposed to homograft tissue, but not late rejection. Mortality/retransplantation rate was significantly higher and allograft survival lower in CHD hearts with excessive fibrosis of one or both ventricles. Anatomic diagnosis at pathologic examination differed from the clinical diagnosis in eight cases. CONCLUSIONS: Survival was better for the cardiomyopathy group and patients >10 years at HT. Prior homograft use was associated with a higher prevalence of early rejection. Ventricular fibrosis (of explant) was a strong predictor of outcome in the CHD group. We presented several pathologic findings in explanted pediatric hearts.

On Personality Measures and Their Data: A Classification of Measurement Approaches and Their Recommended Uses.

We employ a new approach for classifying methods of personality measurement such as self-judgment, mental ability, and lifespace measures and the data they produce. We divide these measures into two fundamental groups: personal-source data, which arise from the target person's own reports, and external-source data, which derive from the areas surrounding the person. These two broad classes are then further divided according to what they target and the response processes that produce them. We use the model to organize roughly a dozen kinds of data currently employed in the field. With this classification system in hand, we describe how much we might expect two types of measures of the same attribute to converge-and explain why methods often yield somewhat different results. Given that each measurement method has its own strengths and weaknesses, we examine the pros and cons of selecting a given type of measure to assess a specific area of personality.

Burden with No Benefit: Prior Authorization in Congenital Cardiology.

Prior authorization is a process that health insurance companies use to determine if a patient's health insurance will cover certain medical treatments, procedures, or medications. Prior authorization requests are common in adult congenital and pediatric cardiology (ACPC) due to need for advanced diagnostics, complex procedures, disease-specific medications, and the heterogeneity of the ACPC population. Prior authorizations in ACPC are rarely denied, but nonetheless, they are often accompanied by significant administrative burden on clinical care teams and delays in patient care. Prior authorizations have been implicated in worsening care inequities. The prior authorization process is insurer specific with differences between commercial and public insurers. Prior authorization rejections were previously found to be more common for women, racial minorities, those with low education, and in low-income groups. Prior authorization unduly burdens routine diagnostics, routine interventional and surgical procedures, and routine cardiac specific medication use in the ACPC population. This manuscript highlights the burdens of prior authorization and advocates for the elimination of prior authorization for ACPC patients.

Cultural and regulatory factors influence distribution and trajectory of invasive species in the United States: A wild pig case study.

Since 2012, control of invasive wild pigs (Sus scrofa) in the United States (US) has become a state and national priority due to their propensity to damage agricultural commodities and infrastructure, transmit disease, detrimentally affect ecological processes, and compete with native wildlife for resources. While several life-history characteristics certainly aided their proliferation, the recreational value of wild pigs was likely the stimulus for translocation and subsequent establishment of populations in ≥35 states, causing an annual economic burden of $1.5 billion in the US. Consequently, state-level legislative procedures regarding wild pigs are expanding in scope and priority, but policy among states lacks uniformity. States vary in their treatment of wild pig control based on differing resource appropriations and stakeholder interests. We conducted an evaluation to determine if policy was associated with state-level 1) presence of wild pigs, 2) spatial extent of wild pig population occupancy, and 3) trajectory of wild pig population occupancy. Our results suggest the presence of wild pigs in various states was influenced by hunting preserves and the sale of hunting opportunities. In occupied states, the spatial extent of wild pigs was again associated with the sale of hunting opportunities and a wild pig hunting culture. Finally, the trajectory of state-level wild pig spatial occupancy was positively influenced by the sale of hunting opportunities, and negatively influenced by transportation policies. Based on these findings, we propose state governments standardize transportation policy and fenced hunting regulations across regions of the US in a more prohibitive fashion to diminish range expansion through illegal and negligent introductions via transportation, release, and escapes from game farms. Moreover, in states where wild pigs have yet to establish, we strongly recommend states proactively prohibit transportation through intra- and interstate movement.

E-Pedigrees: a large-scale automatic family pedigree prediction application.

MOTIVATION: The use and functionality of Electronic Health Records (EHR) have increased rapidly in the past few decades. EHRs are becoming an important depository of patient health information and can capture family data. Pedigree analysis is a longstanding and powerful approach that can gain insight into the underlying genetic and environmental factors in human health, but traditional approaches to identifying and recruiting families are low-throughput and labor-intensive. Therefore, high-throughput methods to automatically construct family pedigrees are needed. RESULTS: We developed a stand-alone application: Electronic Pedigrees, or E-Pedigrees, which combines two validated family prediction algorithms into a single software package for high throughput pedigrees construction. The convenient platform considers patients' basic demographic information and/or emergency contact data to infer high-accuracy parent-child relationship. Importantly, E-Pedigrees allows users to layer in additional pedigree data when available and provides options for applying different logical rules to improve accuracy of inferred family relationships. This software is fast and easy to use, is compatible with different EHR data sources, and its output is a standard PED file appropriate for multiple downstream analyses. AVAILABILITY AND IMPLEMENTATION: The Python 3.3+ version E-Pedigrees application is freely available on: https://github.com/xiayuan-huang/E-pedigrees.

National Variation in Congenital Heart Surgery Outcomes.

BACKGROUND: Optimal strategies to improve national congenital heart surgery outcomes and reduce variability across hospitals remain unclear. Many policy and quality improvement efforts have focused primarily on higher-risk patients and mortality alone. Improving our understanding of both morbidity and mortality and current variation across the spectrum of complexity would better inform future efforts. METHODS: Hospitals participating in the Society of Thoracic Surgeons Congenital Heart Surgery Database (2014-2017) were included. Case mix-adjusted operative mortality, major complications, and postoperative length of stay were evaluated using Bayesian models. Hospital variation was quantified by the interdecile ratio (IDR, upper versus lower 10%) and 95% credible intervals (CrIs). Stratified analyses were performed by risk group (Society of Thoracic Surgeons-European Association for Cardiothoracic Surgery [STAT] category) and simulations evaluated the potential impact of reductions in variation. RESULTS: A total of 102 hospitals (n=84 407) were included, representing ≈85% of US congenital heart programs. STAT category 1 to 3 (lower risk) operations comprised 74% of cases. All outcomes varied significantly across hospitals: adjusted mortality by 3-fold (upper versus lower decile 5.0% versus 1.6%, IDR 3.1 [95% CrI 2.5-3.7]), mean length of stay by 1.8-fold (19.2 versus 10.5 days, IDR 1.8 [95% CrI 1.8-1.9]), and major complications by >3-fold (23.5% versus 7.0%, IDR 3.4 [95% CrI 3.0-3.8]). The degree of variation was similar or greater for low- versus high-risk cases across outcomes, eg, ≈3-fold mortality variation across hospitals for STAT 1 to 3 (IDR 3.0 [95% CrI 2.1-4.2]) and STAT 4 or 5 (IDR 3.1 [95% CrI 2.4-3.9]) cases. High-volume hospitals had less variability across outcomes and risk categories. Simulations suggested potential reductions in deaths (n=282), major complications (n=1539), and length of stay (101 183 days) over the 4-year study period if all hospitals were to perform at the current median or better, with 37% to 60% of the improvement related to the STAT 1 to 3 (lower risk) group across outcomes. CONCLUSIONS: We demonstrate significant hospital variation in morbidity and mortality after congenital heart surgery. Contrary to traditional thinking, a substantial portion of potential improvements that could be realized on a national scale were related to variability among lower-risk cases. These findings suggest modifications to our current approaches to optimize care and outcomes in this population are needed.

Management of Complex Left Ventricular Outflow Tract Obstruction: A Comparison of Konno and Modified Konno Techniques.

Management of complex left ventricular outflow tract obstruction (LVOTO) can be achieved with a Konno or Modified Konno procedure to enlarge the LVOT. We hypothesized that patients who undergo a Modified Konno procedure would have a higher rate of LVOT re-intervention compared to the Konno procedure. Patients who underwent a Konno or Modified Konno procedure for LVOTO at a single tertiary care center between 1990 and 2014 were retrospectively reviewed. The primary outcome was LVOT re-intervention post-discharge from index Konno or Modified Konno procedure. Cox regression and Kaplan-Meier estimates were used for time-to-event analysis of LVOT re-interventions, any unplanned re-interventions, and transplant-free survival. The study included 122 patients: 51 (41.8%) in the Konno group and 71 (58.2%) in the Modified Konno group. Median age at surgery was 8.2 (IQR 3-16) years in the Konno group and 3.9 (IQR 1.5-11) years in the Modified Konno group. Multiple left heart lesions were less prevalent in Modified Konno patients. There were 36 (29.5%) patients with LVOT re-interventions: 8 (16%) in the Konno group and 28 (39.4%) in the Modified Konno group (p = 0.01). Transplant-free survival at five years was 87.2% for the Konno group and 93.5% for the Modified Konno group. A higher rate of LVOT re-intervention was found in the Modified Konno group although the Konno and Modified Konno techniques were applied to different patient populations. This finding suggests that careful preoperative decision-making can direct therapy appropriately and that fundamental diagnosis affects procedure choice.

Economic Evaluation of an Extended Telehealth Worksite Exercise Intervention to Reduce Lost Work Time from Low Back Pain in Career Firefighters.

Purpose Low back pain (LBP) is a leading cause of lost work time (LWT) in firefighters and is related to poor muscle endurance. Although exercise can improve muscle endurance, it must be continued to sustain benefits, and it is unknown if it can reduce LWT. This study conducted an economic evaluation of an extended worksite exercise intervention in career firefighters. Methods A randomized controlled trial allocated 264 firefighters to telehealth with remote instruction ("telehealth"), direct exercise supervision ("direct"), or brief education ("control"). The telehealth and direct groups performed worksite exercises twice weekly for 12 months. Outcomes included quality adjusted life years, LWT from LBP (24-h shifts), costs of LWT from LBP, and net monetary benefits. Results A total of 216 firefighters were included in the economic analysis (telehealth n = 71, direct n = 75, control n = 70). Sixteen experienced LWT from LBP (telehealth n = 4, direct n = 4, control n = 8). The mean number of 24-h shifts lost from LBP were 0.05 (telehealth), 0.28 (direct), and 0.43 (control). Mean study intervention costs per participant were $1984 (telehealth), $5269 (direct), and $384 (control). Net monetary benefit was $3573 for telehealth vs. direct, - $1113 for telehealth vs. control, and - $4686 for direct vs. control. Conclusions Worksite exercise reduced LWT from LBP in firefighters. Telehealth was less costly and more effective at reducing LWT from LBP than direct exercise supervision. If the costs of telehealth were further reduced, a positive net monetary benefit might also be achieved when compared to no intervention.Clinical trial registration: (clinicaltrials.gov): NCT02362243.

Stepwise Construction of Disulfides in Peptides.

The disulfide bond plays an important role in biological systems. It defines global conformation, and ultimately the biological activity and stability of the peptide or protein. It is frequently present, singly or multiply, in biologically important peptide hormones and toxins. Numerous disulfide-containing peptides have been approved by the regulatory agencies as marketed drugs. Chemical synthesis is one of the prerequisite tools needed to gain deep insights into the structure-function relationships of these biomolecules. Along with the development of solid-phase peptide synthesis, a number of methods of disulfide construction have been established. This minireview will focus on the regiospecific, stepwise construction of multiple disulfides used in the chemical synthesis of peptides. We intend for this article to serve a reference for peptide chemists conducting complex peptide syntheses and also hope to stimulate the future development of disulfide methodologies.

When people estimate their personal intelligence who is overconfident? Who is accurate?

OBJECTIVE: We explore accurate self-knowledge versus overconfidence in personal intelligence-a "broad" intelligence about personality. The theory of personal intelligence proposes that people vary in their ability to understand the traits, goals, plans, and actions of themselves and others. We wondered who accurately knew that they were higher in personal intelligence and who did not, and whether individuals with more accurate estimates were distinguishable from others in their psychological characteristics. METHOD: Three archival data sets were identified that included both self-estimates and objective measures of personal intelligence: The measures were the Self-Estimated Personal Intelligence scale and the Test of Personal Intelligence. RESULTS: People who were over-confident-overestimating their ability-level of personal intelligence-were positive in their outlook and more sociable. People who provided the most accurate self-estimates were higher in verbal and personal intelligences, more open, and more conscientious than others. CONCLUSIONS: People who were accurate about themselves have not been studied before in this context but may, for example, serve as the monitors and thinkers who help keep themselves and others reasonable and on track.

An Integrated Approach to Personality Assessment Based on the Personality Systems Framework.

Psychologists who carry out personality assessments must be conversant in diverse technical languages to describe their clients' social contexts and inner personality function. The clinician needs to understand a person's family, gender role, ethnic identity, religious beliefs, and similar qualities, and also a client's inner personality functioning, including the workings of motives, emotions, cognition, and self-control: These can be characterized by relevant psychiatric symptoms, personality traits, and individual test scores such as those on the MMPI-2-RF and Rorschach-Performance Assessment System. The Personality Systems Framework for Assessment (PSF-A) can support the assessment process by organizing information about both an individual's context and personality function, freeing professionals to optimally focus on characterizing their clients.

Applying family analyses to electronic health records to facilitate genetic research.

Motivation: Pedigree analysis is a longstanding and powerful approach to gain insight into the underlying genetic factors in human health, but identifying, recruiting and genotyping families can be difficult, time consuming and costly. Development of high throughput methods to identify families and foster downstream analyses are necessary. Results: This paper describes simple methods that allowed us to identify 173 368 family pedigrees with high probability using basic demographic data available in most electronic health records (EHRs). We further developed and validate a novel statistical method that uses EHR data to identify families more likely to have a major genetic component to their diseases risk. Lastly, we showed that incorporating EHR-linked family data into genetic association testing may provide added power for genetic mapping without additional recruitment or genotyping. The totality of these results suggests that EHR-linked families can enable classical genetic analyses in a high-throughput manner. Availability and implementation: Pseudocode is provided as supplementary information. Contact: HEBBRING.SCOTT@marshfieldresearch.org. Supplementary information: Supplementary data are available at Bioinformatics online.

Machine learning for phenotyping opioid overdose events.

OBJECTIVE: To develop machine learning models for classifying the severity of opioid overdose events from clinical data. MATERIALS AND METHODS: Opioid overdoses were identified by diagnoses codes from the Marshfield Clinic population and assigned a severity score via chart review to form a gold standard set of labels. Three primary feature sets were constructed from disparate data sources surrounding each event and used to train machine learning models for phenotyping. RESULTS: Random forest and penalized logistic regression models gave the best performance with cross-validated mean areas under the ROC curves (AUCs) for all severity classes of 0.893 and 0.882 respectively. Features derived from a common data model outperformed features collected from disparate data sources for the same cohort of patients (AUCs 0.893 versus 0.837, p value = 0.002). The addition of features extracted from free text to machine learning models also increased AUCs from 0.827 to 0.893 (p value < 0.0001). Key word features extracted using natural language processing (NLP) such as 'Narcan' and 'Endotracheal Tube' are important for classifying overdose event severity. CONCLUSION: Random forest models using features derived from a common data model and free text can be effective for classifying opioid overdose events.

Validity of the Multidimensional Task Ability Profile.

Background The Multidimensional Task Ability Profile (MTAP) is a patient-reported outcome (PRO) measure that provides a global score linked to the physical demand characteristics of work, but needs to be validated against established measures. Purpose To assess the concurrent validity of the MTAP compared with the Oswestry Disability Index (ODI), Neck Disability Index (NDI), Disabilities of the Arm, Shoulder, and Hand (DASH), Lower Extremity Functional Scale (LEFS), and Short Form 12 Health-Related Quality of Life (SF-12) questionnaires. Methods An observational study was conducted in 157 patients undergoing musculoskeletal rehabilitation. At baseline and after 30 days of treatment, patients completed the MTAP, ODI, NDI, DASH, LEFS, and SF-12 and provided self-reported work status. Results At baseline and after 30 days, convergent validity between the MTAP and DASH, LEFS, NDI, and ODI was good to excellent. Concurrent validity between the MTAP and SF-12 physical component score (PCS) and mental component score (MCS) was moderate or fair, respectively. Sensitivity to change over the 30-day treatment interval was established for the MTAP, SF-12 PCS, SF-12 MCS, and LEFS. Fair to moderate predictive validity for work status was found for the MTAP, ODI, NDI, DASH, and SF-12 PCS. Conclusions The MTAP demonstrated adequate concurrent validity, predictive validity, and sensitivity to change compared to other PROs. For patients with various impairment types, the MTAP may be a useful omnibus measure to supplement specialty instruments such as the DASH, NDI, ODI, or LEFS.

Peptide Conjugates with Small Molecules Designed to Enhance Efficacy and Safety.

Peptides constitute molecular diversity with unique molecular mechanisms of action that are proven indispensable in the management of many human diseases, but of only a mere fraction relative to more traditional small molecule-based medicines. The integration of these two therapeutic modalities offers the potential to enhance and broaden pharmacology while minimizing dose-dependent toxicology. This review summarizes numerous advances in drug design, synthesis and development that provide direction for next-generation research endeavors in this field. Medicinal studies in this area have largely focused upon the application of peptides to selectively enhance small molecule cytotoxicity to more effectively treat multiple oncologic diseases. To a lesser and steadily emerging extent peptides are being therapeutically employed to complement and diversify the pharmacology of small molecule drugs in diseases other than just cancer. No matter the disease, the purpose of the molecular integration remains constant and it is to achieve superior therapeutic outcomes with diminished adverse effects. We review linker technology and conjugation chemistries that have enabled integrated and targeted pharmacology with controlled release. Finally, we offer our perspective on opportunities and obstacles in the field.

Synthetic Advances in Insulin-like Peptides Enable Novel Bioactivity.

Insulin is a miraculous hormone that has served a seminal role in the treatment of insulin-dependent diabetes for nearly a century. Insulin resides within in a superfamily of structurally related peptides that are distinguished by three invariant disulfide bonds that anchor the three-dimensional conformation of the hormone. The additional family members include the insulin-like growth factors (IGF) and the relaxin-related set of peptides that includes the so-called insulin-like peptides. Advances in peptide chemistry and rDNA-based synthesis have enabled the preparation of multiple insulin analogues. The translation of these methods from insulin to related peptides has presented unique challenges that pertain to differing biophysical properties and unique amino acid compositions. This Account presents a historical context for the advances in the chemical synthesis of insulin and the related peptides, with division into two general categories where disulfide bond formation is facilitated by native conformational folding or alternatively orthogonal chemical reactivity. The inherent differences in biophysical properties of insulin-like peptides, and in particular within synthetic intermediates, have constituted a central limitation to achieving high yield synthesis of properly folded peptides. Various synthetic approaches have been advanced in the past decade to successfully address this challenge. The use of chemical ligation and metastable amide bond surrogates are two of the more important synthetic advances in the preparation of high quality synthetic precursors to high potency peptides. The discovery and application of biomimetic connecting peptides simplifies proper disulfide formation and the subsequent traceless removal by chemical methods dramatically simplifies the total synthesis of virtually any two-chain insulin-like peptide. We report the application of these higher synthetic yield methodologies to the preparation of insulin-like peptides in support of exploratory in vivo studies requiring a large quantity of peptide. Tangentially, we demonstrate the use of these methods to study the relative importance of the IGF-1 connecting peptide to its biological activity. We report the translation of these finding in search of an insulin analog that might be comparably enhanced by a suitable connecting peptide for interaction with the insulin receptor, as occurs with IGF-1 and its receptor. The results identify a unique receptor site in the IGF-1 receptor from which this enhancement derives. The selective substitution of this specific IGF-1 receptor sequence into the homologous site in the insulin receptor generated a chimeric receptor that was equally capable of signaling with insulin or IGF-1. This novel receptor proved to enhance the potency of lower affinity insulin ligands when they were supplemented with the IGF-1 connecting peptide that similarly enhanced IGF-1 activity at its receptor. The chimeric insulin receptor demonstrated no further enhancement of potency for native insulin when it was similarly prepared as a single-chain analogue with a native IGF-1 connecting peptide. These results suggest a more highly evolved insulin receptor structure where the requirement for an additional structural element to achieve high potency interaction as demonstrated for IGF-1 is no longer required.

Max Bergmann award lecture:Macromolecular medicinal chemistry as applied to metabolic diseases.

This review presents the scope of research presented in an October 2016 lecture pertaining to the award of the 2015 Max Bergmann Medal. The advancement in synthetic and biosynthetic chemistry as applied to the discovery of novel macromolecular drug candidates is reviewed. The evolution of the technology from the design, synthesis, and development of the first biosynthetic peptides through the emergence of peptide-based incretin agonists that function by multiple biological mechanisms is exemplified by the progression of such peptides from preclinical to clinical study. A closing section highlights recent progress made in total chemical synthesis of insulin and related peptides.

Accurate Prediction of Congenital Heart Surgical Length of Stay Incorporating a Procedure-Based Categorical Variable.

OBJECTIVES: There is increasing demand for the limited resource of Cardiac ICU care. In this setting, there is an expectation to optimize hospital resource use without restricting care delivery. We developed methodology to predict extended cardiac ICU length of stay following surgery for congenital heart disease. DESIGN: Retrospective analysis by multivariable logistic regression of important predictive factors for outcome of postoperative ICU length of stay greater than 7 days. SETTING: Cardiac ICU at Boston Children's Hospital, a large, pediatric cardiac surgical referral center. PATIENTS: All patients undergoing congenital heart surgery at Boston Children's Hospital from January 1, 2010, to December 31, 2015. INTERVENTIONS: No study interventions. MEASUREMENTS AND MAIN RESULTS: The patient population was identified. Clinical variables and Congenital Heart Surgical Stay categories were recorded based on surgical intervention performed. A model was built to predict the outcome postoperative ICU length of stay greater than 7 days at the time of surgical intervention. The development cohort included 4,029 cases categorized into five Congenital Heart Surgical Stay categories with a C statistic of 0.78 for the outcome ICU length of stay greater than 7 days. Explanatory value increased with inclusion of patient preoperative status as determined by age, ventilator dependence, and admission status (C statistic = 0.84). A second model was optimized with inclusion of intraoperative factors available at the time of postoperative ICU admission, including cardiopulmonary bypass time and chest left open (C statistic 0.87). Each model was tested in a validation cohort (n = 1,008) with equivalent C statistics. CONCLUSIONS: Using a model comprised of basic patient characteristics, we developed a robust prediction tool for patients who will remain in the ICU longer than 7 days after cardiac surgery, at the time of postoperative ICU admission. This model may assist in patient counseling, case scheduling, and capacity management. Further examination in external settings is needed to establish generalizability.

The Global Spine Care Initiative: resources to implement a spine care program.

PURPOSE: The purpose of this report is to describe the development of a list of resources necessary to implement a model of care for the management of spine-related concerns anywhere in the world, but especially in underserved communities and low- and middle-income countries. METHODS: Contents from the Global Spine Care Initiative (GSCI) Classification System and GSCI care pathway papers provided a foundation for the resources list. A seed document was developed that included resources for spine care that could be delivered in primary, secondary and tertiary settings, as well as resources needed for self-care and community-based settings for a wide variety of spine concerns (e.g., back and neck pain, deformity, spine injury, neurological conditions, pathology and spinal diseases). An iterative expert consensus process was used using electronic surveys. RESULTS: Thirty-five experts completed the process. An iterative consensus process was used through an electronic survey. A consensus was reached after two rounds. The checklist of resources included the following categories: healthcare provider knowledge and skills, materials and equipment, human resources, facilities and infrastructure. The list identifies resources needed to implement a spine care program in any community, which are based upon spine care needs. CONCLUSION: To our knowledge, this is the first international and interprofessional attempt to develop a list of resources needed to deliver care in an evidence-based care pathway for the management of people presenting with spine-related concerns. This resource list needs to be field tested in a variety of communities with different resource capacities to verify its utility. These slides can be retrieved under Electronic Supplementary Material.